1. Field of the Invention
The present invention relates to nicotinanilide compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds, and to methods for their use in various therapies.
2. Description of the Related Art
Chemotactic cytokines (chemokines) are a class of potent inflammatory mediators that have the potential to attract specific subsets of leukocytes to sites of inflammation. Chemokines are typically low-molecular-mass (7–9 kd) proteins that can be divided into four subfamilies (CCC or β-subfamily, CXC or α-subfamily, CX3C) and are categorized by their primary amino acid structure. The CXC subfamily is characterized by the two conserved Cys residues (C) near the N-terminus and separated by an amino acid (X). Some of the CXC chemokines, of which IL-8 and GRO-α are representative, belong further to the ELR+ subfamily (Glu-Leu-Arg) and are important in the recruitment and activation of neutrophils via the CXCR1 and CXCR2 receptors.
The interaction of chemokines with specific cell populations is mediated by G-protein-coupled seven-transmembrane receptors (7TMR). Chemokine receptors can be classified into four groups (CR, CCR, CXCR, CX3CR) based upon their primary amino acid sequence. The CXCR1 receptor binds with high affinity to IL-8 and low affinity to NAP-2, ENA-78 (epithelial cell-derived neutrophil-activating factor), GRO-α, -β, and -γ, whereas, CXCR2 binds with high affinity to all of the mentioned CXC chemokines. Both CXCR1 and CXCR2 receptors are found primarily on neutrophils and a subset of T-cells. W. Holmes et al., Science 253:1278 (1991); P. Murphy et al., Science 253:1280 (1991); A. Chuntharapai et al., J. Immunol. 153:5682 (1994); L. Xu et al., J. Leukocyte Biol. 57:335 (1995).
CXCR1 and CXCR2 have been shown to mediate the responses to CXC chemokines in neutrophils (polymorphonuclear neutrophils; PMN) and are essential to the acute inflammatory response. P. Grob et al., J. Biol. Chem. 265:8311 (1990); J. Besemer et al., J. Biol. Chem. 264:17, 409 (1989); A. Samanta et al., J. Exp. Med. 169:1185 (1989); W. Holmes et al., Science 253:1280 (1991); P. Murphy et al., Science 253:1280 (1991). Although both receptors are involved in neutrophil chemotaxis, in vitro studies using human neutrophils have shown inconclusively if chemotaxis is mediated by one or both receptors. IL-8 induced chemotaxis studies using anti-receptor monoclonal antibodies in CXCR1 and CXCR2 cell lines have led to conflicting reports. J. Quan et al., Biochem. Biophys. Res. Commun. 219:405 (1996); A. Chuntharapai et al., J. Immunol. 155:2587 (1995); M. Hammond et al., J. Immunol. 155:1428 (1995). There is also evidence to indicate that the transendothelial migration of CLA+ T-cells is a CXCR2 mediated event. L. Santamaria-Babi et al., Eur. J. Immunol. 26:2056 (1996).
The role, in inflammatory disorders, of neutrophil chemotaxis mediated by the CXCR1 and CXCR2 receptors is generally accepted. It has been reported that neutrophils are implicated in the pathogenesis of the acute respiratory distress syndrome (ARDS) in patients with sepsis. J. Repine et al., Am. Rev. Respir. Dis. 144:251 (1991). A causal role of PMNs in the lung injury associated with trauma is also widely accepted. G. Goldman et al., Ann. Surg. 212:513 (1990); S. Linas et al., Am. J. Physiol. 255:F728 (1988); R Simpson et al., Prog. Clin. Biol. Res. 388:265 (1994); S. Donnelly, Arch. Emerg. Med. 10:108 (1993); S. Donnelly, Resuscitation 28:87 (1994). For example, sepsis-related ARDS patients have increased levels of IL-8, ENA-78, ad GRO-α in their bronchoalveolar lavage fluids. R. Goodman et al., Am. J. Respir. Crit. Care Med. 154:602 (1996); J. Villard, Am. J. Respir. Crit. Care Med. 152:1549 (1995). Additionally, it has been demonstrated that CXCR1 functions as the single dominant CXC chemokine receptor for neutrophil chemotaxis in patients with sepsis. C. Cummings, J. Immunol. 162:2341 (1999).
High levels of IL-8 and tissue neutrophil infiltration have been observed in the synovial tissues of rheumatoid arthritis patients (H. Endo, Lymphokine Cytokine Res. 10:245 (1991)). Evidence has been presented that GRO-α and IL-8 are important mediators involved in the recruitment of neutrophils in the early and late phases of lipopolysaccharide-induced (LPS) rabbit arthritis. A. Matsukawa et al., Lab. Invest. 79:591 (1999). The murine CXCR2 receptor has also been shown to be necessary for neutrophilic inflammation in a mouse model of gouty synovitis. R. Terkeltaub et al., Arthritis. Rheum. 41:900 (1998).
CXC chemokines have attracted attention as being important in the development of atherosclerosis. R. Terkeltaub et al., Curr. Opin. Lipidol. 9:397 (1998). The role of CXCR1 and CXCR2 ligands on monocyte function in atherosclerosis in rabbits was published by D. Schwartz et al., J. Clin. Invest 94:1968 (1994). Knockout mice that lacked CXCR2 expression had diminished lesion size. W. Boisvert et al., J. Clin. Invest. 101:353 (1998).
The involvement of the CXCR2 receptor in the pathological inflammatory response elicited by central nervous system (CNS) cells as related to Alzheimer's disease is also gaining significant attention. M. Xia et al., J. Neurovirol. 5:32 (1999). Reports have focused on the upregulation of CXCR2 expression on dystrophic neurites of senile plaques. M Xia et al., Am. J. Pathol. 150:1267 (1997); R. Horuk et al., J. Immunol. 158:2882 (1997).
High levels of IL-8 and neutrophil infiltration have been observed in the pathogenesis of a number of other disease indications. This includes ulcerative colitis (Y. Mahida, Clin. Sci. 82:273 (1992); R. Izzo, Am. J. Gastroenterol 87:1447 (1992)) and psoriasis (R. Gillitzer et al., J. Invest. Dermatol. 107:778 (1996); T. Kojima, J. Invest. Dermatol. 101:767 (1993)). CXCR1 and CXCR2 chemokines and their roles in tumor growth and metastasis have been reviewed. J. Wang, J. Immunol. Meth. 220:1 (1998).
To date, a limited number of CXCR1 and CXCR2 antagonists have been reported. It was reported that a bis-aryl urea was able to selectively inhibit CXCR2 and prevent neutrophil migration and chemotaxis in a rabbit model. J. White, J. Biol. Chem. 273:10095 (1998). Other CXCR1 and CXCR2 receptor antagonists have focused on NH2-terminal truncations and modifications of IL-8, GRO-α, and ELR motifs. S. Jones et al., J. Biol. Chem. 272:16166. Murine neutrophil recruitment in vivo could also be inhibited via CXCR2 receptor blocking using a truncated human GRO-α analog. There are currently no CXCR1 or CXCR2 receptor antagonist based therapies widely available.
There is a continued need for inhibitors of chemokine-mediated cellular events, such as those giving rise to an inflammatory response. Small molecule antagonists of CXC receptors and their ligands such as GRO-α and IL-8 would be useful in the control of harmful inflammatory processes as well as important tools for the investigation of receptor-ligand interactions.